This application seeks renewal of a Program Project Grant (PPG) that is now in its 40th year of continuous funding making it currently the longest running PPG in the Lung Division at the NIH/NHLBI. Part of the success of the 40 plus years of this program owes to the fact that is has continuously evolved since its inception. The program thrives on bringing together the best scientific expertise to pursue the most cutting edge investigations in the field, building on novel and exciting findings of its investigators and of th pulmonary vascular community in general. This renewal, in line with this overall mission and goals, now addresses in three highly integrated and mechanistic projects the role of inflammation and more specifically the role of macrophages in the vascular remodeling that characterizes the most frequent forms of chronic pulmonary hypertension (PH). Our proposal, focuses directly on inflammation as one of the key pathogenetic features of PH as defined in the 2013 World Symposium on Pulmonary Hypertension in Nice. Importantly, this requires the careful consideration of the clinical, pathological, and possibly pathobiological heterogeneity of PH, which is manifested by its complex classification. As apparent through the scope of the three projects led by Dr. Stenmark (Project 1), Dr. Tuder (Project 2) and Dr. Nicolls (Project 3) and the overall infrastructure of this PPG application (four supporting Cores; Administrative, Clinical, Histopathology and Animal), we are poised to provide novel insights into the complex cellular and molecular pathophysiology of inflammation in various forms of PH, hopefully leading to identification of translatable new therapeutic approaches for human forms of the disease. The diversity of the systems that will be used to answer questions regarding inflammation in PH is a significant strength in the current proposal which can hardly be duplicated by individual investigators/institutions. Thus, it will allow investigation of the commonality of macrophage (and probably fibroblast) involvement in different models, and likely human varieties of PH, while also allowing us to address exciting differences in pathways leading to these central activities. Collectively, our investigations will ultimately provide key data in elucidating the role of inflammation as a cause/contributor, a bystander, or whether and when it is simply the end result of the disease process, a critical step to advance our understanding of chronic pulmonary vascular disease in order to significantly impact the clinical management of PH. (End of Abstract) PROJECT 1: CROSSTALK BETWEEN METABOLISM AND INFLAMMATION IN PULMONARY HYPERTENSION (Stenmark, Kurt)